Work package 2: Pharmaceutical Development
Description of the work package
Prof. Dr. Jörg Breitkreutz from Ethicare GmbH is leading this work package and thus takes over the responsibility for the pharmaceutical aspects of the LENA project.
Based on preliminary work on minitablets, and using technical batches with 0.25 mg and 1.00 mg enalapril maleate procured from eligible and reliable sources, the analytical methods appropriate for characterization will be developed and evaluated by Ethicare in this work package.
Ethicare will monitor the production of the clinical batches at NextPharma, a contracted manufacturer, and will ensure compliance with GMP regulations – both for the relative bioavailability study in healthy volunteers and for the clinical studies in paediatric subpopulations in work package 8, work package 9, and work package 10.
The recorded quality and stability data will be used for the finalization of the Investigational Medicinal Product Dossiers (IMPD) for the studies prepared by Ethicare in this work package and the Investigator Brochure (IB) prepared by Ethicare and Pharmaplex. These documents will later be continuously updated for the clinical studies in children by Ethicare and Pharmaplex. The Paediatric Investigation Plan (PIP) to be submitted to the EMA will be prepared in cooperation with Ethicare, with the final aim of preparing all necessary documentation for filing a Paediatric Use Marketing Authorization (PUMA) by the pharmaceutical sponsor to be identified in work package 14.
Our tasks in work package are described below:
- To source suitable starting materials: Ethicare will source the market for the Active Pharmaceutical Ingredient (API) enalapril maleate, age-appropriate pharmaceutical excipients and suitable packaging materials and containers. Detailed information on each of these components will be a mandatory part of all regulatory documents, and the selection of these components will have to be finalized prior to the start of pharmaceutical development program.
- Development of appropriate drug formulations and characterization methods: Suitable formulations for 0.25 and 1.00 mg API-containing orodispersible minitablets will be developed and evaluated for practical use, age-appropriateness and regulatory compliance with the recent European Medicines Agency’s (EMA) “Guideline on pharmaceutical development of medicines for paediatric use”. The relevant product specifications for the formulations to be used in the studies will be finalized by Ethicare.
- Production of investigational medicinal batches for bioavailability study in adults: Detailed specifications regarding the formulations and analytical methods will be transferred to the contract manufacturer. A clinical batch with single doses of 10 orodispersible minitablets containing 1,0 mg enalapril maleate each in a plastic container will be prepared under Good Manufacturing Practice (GMP) guidelines at the manufacturer’s facilities, released for investigational medicinal use by the company’s Qualified Person, and distributed to the site conducting the bioavailability study in healthy adult volunteers. The investigational medicinal products used in the relative bioavailability study in adults will be subjected to short-term stability experiments to confirm the stability of the medication. Results of these stability experiments will be used later as proof of the stability of the investigational medicinal products used in the clinical studies in children.
- Produce investigational medicinal batches for paediatric clinical studies: At least three clinical batches per dose strength will be prepared under Good Manufacturing Practice (GMP) guidelines at the manufacturer’s facilities, released for investigational medicinal use by the company’s Qualified Person, and distributed to the clinical sites of the consortium. As mentioned above, results of the short-term stability experiments conducted as part of the bioavailability study in healthy adult volunteers will be used to prove the stability of the study medication to be used in later clinical batches for the clinical studies in paediatric patients.
- Investigate stability of the produced batches: A full scale stability assessment according to ICH/EMA regulations will be performed on the minitablet batches (three per dose strength) to investigate the influence of different humidity and temperature conditions, to confirm the clinical availability over time, and to establish an expiry date. Further, an in-use stability study will be performed simulating the routine use of the minitablets in a multidose container. Out-of-specification results, if they occur, will be used to improve formulation, packaging and/or handling properties.
- Prepare summary report and regulatory documents: The effort put into this task will provide comprehensive formulation development data which will then be included in IMPDs, IBs, the PIP, and the Summary Report at the time of submission to the competent authorities, including Ethical Boards of the clinical sites, national regulatory bodies and the EMA. The formulation development data used in the different submission formats will be transferred into one electronic common technical document (eCTD) format required by the EMA for PUMA submissions.